From Beyond The Rainbow Somewhere

Siddhartha Mukherjee

Post navigation

Despite flaws, this lively and accessible history of the gene and its implications for the future is bursting with complex ideas

In 2010, researchers launched a study, the Strong African American Families project, in one of the bleakest, most impoverished areas of rural Georgia, a place overrun by alcoholism, violence, mental illness and drug use. “Abandoned clapboard houses with broken windows dot the landscape,” Siddhartha Mukherjee tells us. “Crime abounds. Vacant parking lots are strewn with hypodermic needles. Half the adults lack a high school education and nearly half the families have single mothers.” You get the picture.

The scientists wanted to know how an individual’s genetic makeup might help or hinder their chances of surviving this grim background, and so began testing local families to determine which variant of a gene known as 5-HTTLRP they possessed. One, known as the short variant, had previously been linked to individuals prone to depression, alcoholism and anxiety. The other, the long variant, was associated with relative “normality”.

Sure enough, the scientists found that possessors of short variants were more likely to binge drink, use drugs and be sexually permissive. Combine a deprived background with a set of “bad” genes and your chance in life was doomed, it appeared. But the researchers went further, providing counselling for short-variant binge drinkers and long-variant “normals” to see how each group responded to help from others. They found the former group, while more prone to antisocial behaviour, was also more likely to react positively to counselling. That grim start to life was not quite so hopeless as it seemed. “It is as if resilience itself has a genetic core,” says Mukherjee in this broad-ranging guide to modern genetics and its impact on life.

The idea of a resilience gene has since taken root, leading psychologists to propose that susceptible short-variant children – the worst behaved but better at responding to counselling – be targeted for scarce and costly intervention. To his credit, Mukherjee is suspicious of the ethics of a scheme whereby an authority, having genotyped children in a particular area, could then be allowed to choose who is worthy of the attention of the best teachers and the most resources and who is not. Put that way, the notion looks unpleasant.

The trouble, says Mukherjee, is that we are going to encounter this sort of thing increasingly often as our ability to unravel the DNA of our fellow citizens becomes more powerful. And that refers not just to interventions we might make in a person’s upbringing but to those whose DNA we may be able to change. Already scientists are finding ways to alter the genetic makeup of children with harmful mutations including cystic fibrosis and muscular dystrophy. Soon, we will start to tackle more complex disorders – cancers or heart diseases – by altering or replacing entire groups of genes. “We have reached the stage where, as intelligent organisms, we are learning how to read the instructions for our own creation,” says Mukherjee. “Soon we will be ready to write our own instructions. In other words, we will be able to manipulate our own genetic future, snipping genes from embryos or adding new ones.”

Mukherjee is excellent on the ethical problems that will be presented by our growing ability to unpick the DNA of our fellow citizens.

The question is: who will choose what procedures are acceptable and who receives them? And what might be the unintended consequences? Illness might progressively vanish, but so might identity, if we tinker too much, says Mukherjee. Similarly, grief might be diminished but so might tenderness.

These are intriguing questions and, in trying to find answers, Mukherjee takes us on a journey that begins with the tribulations of his own family. He has two uncles and a cousin affected by schizophrenia and bipolar disorder; the question of whether he and his relatives are affected by a genetic predisposition to the conditions clearly concerns him. “Madness, it turns out, has been among the Mukherjees for at least two generations,” we are told. This is Mukherjee’s intimate history and it is touchingly related – though in truth it only forms an intermittent part of his narrative. The major part of The Gene is made up of a sweeping history of genetics that takes us from its dawn – with the garden pea experiments of Gregor Mendel, who revealed the existence of individual units of heritability – to modern gene-editing techniques, which allow scientists to alter or replace genes more or less at their leisure. It is an ambitious trip, to say the least.

Fortunately, Mukherjee is an assured, polished wordsmith – his previous work, on cancer, The Emperor of All Maladies, won a Pulitzer – who displays a penchant for the odd adroit aphorism and well-placed pun. Thus Mendel, who gave up his research on rodents to work instead with garden vegetables, is praised for “giving peas a chance” while genes are described, rather neatly, as pixels of heredity. Genes are described, rather appositely, as “pixels of heredity”, while the Virginia Colony for Epileptics and Feebleminded, sanctioned in 1906 by eugenicists to confine those deemed “socially abnormal”, is likened to a Hotel California of mental illness. “Patients who checked in rarely ever left,” says Mukherjee.

Such efforts are welcome. This is a big book, bursting with complex ideas; without careful presentation, the reader would have struggled. Yet it is not without critics. An extract published last month in the New Yorker attracted strong censure from several biologists for misrepresenting the way our environments can affect the actions of genes, drawing a robust response from Mukherjee.

I have different qualms. For a start, I found the book’s priorities erratic. The key story of how DNA analysis showed Homo sapiens once interbred with our evolutionary cousins, the Neanderthals – the work of Swedish researcher Svante Pääbo – is dismissed in a few paragraphs while page after page is devoted to the work of US geneticist Dean Hamer, who in 1992 claimed to have found a “gay gene” that explained homosexuality in men – even though no gay gene has since been found, Mukherjee eventually admits. So why devote umpteen pages to the subject?

The latter stages of the narrative also present us with a rather irritating American triumphalism, as we progress through the late 20th and early 21st century to our modern mastery of the gene. Mukherjee tells us that, in 1980, David Botstein and his Massachusetts Institute of Technology colleagues were responsible for publishing the first proposal to use DNA variations to create a map of the human genome, a notion crucial to the subsequent launching of the Human Genome Project. In fact, Britain’s Walter Bodmer and Ellen Solomon had already outlined the idea in 1979, in the Lancet. The omission is slipshod.

Fortunately, these flaws do not detract seriously from an otherwise well-written, accessible and entertaining account of one of the most important of all scientific revolutions, one that is destined to have a fundamental impact on the lives of generations to come. The Gene is an important guide to that future.

December 6, 2013

The attendant walked into the hospital waiting room and called my name. I took a deep breath and hurried through the door. “I’m always surprised when my name is pronounced properly at a doctor’s office,” I said.

I lay on the bench and slowly slid into the doughnut-shaped machine. As I did, I noticed the ceiling. It was painted with a scene of sunlight peeking through some leafy branches.

For all the cruel randomness and vagaries of cancer, the disease, as a brand, is extremely consistent. There are the recognizable symbols: the bald head, the yellow wristband, the pink ribbon. There are the well-known treatments: chemotherapy, radiation. There are the familiar expressions: Stage IV, metastases, remission, cure. But of all these elements, perhaps none is more enduring than the metric of the five-year survival rate.

When I first learned that I had aggressive bone cancer in my left leg in 2008, I did what many patients do: I immediately searched out the five-year survival figures. I then did the grim calculation of how old my children would be at that time and whether I would outlive my parents. Over a brutal year of chemo, surgery and rehabilitation, I kept an indelible ticking clock in my head. Sometimes I wondered, “Why won’t the clock speed up?” Other times, “Why won’t it slow down?”

And as I slogged through subsequent years of scans — first every three months, then every four, then every six — and experienced what survivors call “scanxiety,” I imagined what the five-year benchmark would feel like. Like an actor practicing my Oscar acceptance speech, I even rehearsed exactly what I would do: break down in tears, give a party, buy plane tickets to Hawaii.

And yet, as I approached the milestone in recent weeks, I began to feel more ambivalence. What happened? Or, had I been wrong all along?

The concept of the five-year survival rate for cancer was introduced in the 1930s. Initially, the designation was used for blood cancers, which grow fast and were extremely lethal at the time, said Dr. Siddhartha Mukherjee, a cancer specialist at Columbia University Medical Center and the author of “The Emperor of All Maladies,” which won a Pulitzer Prize. For those patients, reaching five years was considered something of a miracle. “The idea was you could define a time point where it would make sense to think about that cancer as being cured,” Dr. Mukherjee said. “From there it crept backward into all cancers.”

By the 1950s, five-year survival figures were becoming standard, and by the early 1970s the National Cancer Institute began releasing regular statistics for most forms of the disease. In the face of such authoritative endorsement, the public accepted these figures as meaningful.

But from the very beginning, many scientists were uneasy with grouping all forms of cancer under one metric of survival. “Five years is quite an arbitrary number,” said Julia Rowland, the director of the National Cancer Institute Office of Cancer Survivorship. “For some cancers, if you haven’t had a recurrence in two years, your rate of recurrence drops considerably. For others, like breast cancer, you can have a recurrence at any time.”

For these reasons (and more), Dr. Mukherjee called the five-year figures a “vestige of the past” and predicted that in the near future they would be replaced with more individualized benchmarks. “Just as it makes sense to personalize cancer therapy, it also makes sense to personalize what survival means to an individual patient,” he said. Until then, he considers the five-year survival figure an “instrument of convenience.” In his book he tells the moving story of delivering flowers to a patient when she reached the date. “I was responding to the iconography,” he said. “We mark birthdays, and if you’re a cancer physician you mark survival days.”

Patients, too, mark survival days. Almost everyone I know who’s been told they have the disease can tell you the date. But how to recognize that “cancerversary,” especially the five-year one, is a source of surprising unease. In conversations with nearly two dozen survivors, I found patients divided almost evenly between those who view their five-year “cancerversary” as a joyous occasion and celebrate with gusto, and those who view it as a more solemn day and acknowledge it with quiet gratitude and continued vigilance.

On the joyful side, one breast cancer survivor told me she held a “queen party” at which she decorated a cake in the shape of Queen Elizabeth’s coronation crown and wore a purple ball gown and crown of jewels. Another told me that on her “five-year celebration day,” her husband treated her to lobster tail and crab legs at Red Lobster.

A veteran of testicular cancer told me that when he hit five years, he felt invincible and started running across streets and dropping his surfboard into disproportionately huge waves. “Then I settled down a bit,” he said. “But I still cannot be killed.”

On the more subdued side, one breast cancer survivor who learned she had the disease in her early 30s told me that every year on her “cancerversary” she sends out “a sappy email to all the wonderful people in my life, thanking them for all they’ve done, and continue to do, to make my life so special.” When she hit five years, she asked her doctor what to think.

“Well, five is better than four,” he said, “but six will be even better.” She’s now at eight.

The parents of a boy who was found to have Stage IV neuroblastoma at age 4 told me that when they approached the five-year mark, they planned a party. “But when the time came, we just felt too superstitious about it,” the mother said. “Why tempt fate?” The boy reached the mark of eight and a half years this week, she said, and is healthy and happy.

As for me, when my oncologist announced that my scans were clean (I had reached five years with no sign of cancer), I did a small fist pump but was otherwise more stone-faced and sober than I had anticipated. I spent a few minutes grilling him about ongoing challenges, and he asked me to come back in a year for my next appointment. When I stepped outside, instead of sobbing uncontrollably as I had after previous scans (and instead of buying those tickets to Hawaii), I stood in silent awe at my good fortune. Unlike winning an Oscar, I had done little to earn this moment. I am among the lucky ones, at least for now: My biology had taken the chemistry. Like anyone in this situation, I have met many who never made it this far.

Four years ago, on the first anniversary of the diagnosis of my cancer, I saw my surgeon, John Healy, and asked what message he would give my daughters if I died. He said he would tell them what he has learned treating this disease for decades. “Everybody dies,” he said. “But not everybody lives. I want you to live.”

That has been my motto ever since: to live. If my cancer comes back, I want to have learned that lesson. If it doesn’t I want to have learned it, too. It’s the message I took from one year; I take it today from five years; and I hope to take every year that I slide back into the doughnut hole and look up at the sun peeking out through the leaves.

“Newspapers may bring us news of a scientific-industrial complex that is increasingly depersonalized … where terabytes of data are churned through supercomputers to generate gigabytes of information,” observed physician-scientist and writer Siddhartha Mukherjee. “But ask a real scientist and you get a profoundly different image of how real science happens.”

Dr. Mukherjee, the author of The Emperor of All Maladies: A Biography of Cancer, which won the 2011 Pulitzer Prize for General Nonfiction, delivered the Commencement address at Memorial Sloan-Kettering’s 2013 Commencement and Academic Convocation. He is an assistant professor of medicine at Columbia University and a staff cancer physician at Columbia University Medical Center.

“Science,” Dr. Mukherjee asserted, “is among the most profoundly human of our activities. Far from being subsumed by the dehumanizing effects of technology, science in fact remains our last stand against it.” Invoking “the indelible image of Gregor Mendel, a monk in wire-rimmed glasses, tending his plants, stooping with paint brush and forceps, to transfer the orange dust of pollen from one flower to the next,” he described a quality he called the “tenderness” of the scientific enterprise.

Tenderness

“It’s not a word typically used to describe science or scientists,” Dr. Mukherjee acknowledged. “It describes a certain intimacy between human beings and nature, a nourishment that must happen before investigation can begin.”

Science is among the most profoundly human of our activities. Far from being subsumed by the dehumanizing effects of technology, science in fact remains our last stand against it.

-Siddhartha Mukherjee

Dr. Mukherjee framed his talk by asking how Mendel, working in the mid-1800s in the garden of his monastery, “stumbled upon what is arguably the most seminal discovery of modern biology: that hereditary information is transmitted from one generation to the next.”

“His science began with tending,” noted Dr. Mukherjee. “The laborious cross-fertilization of seedlings … the markings of wrinkles on seeds [which] led him to findings that could not be explained by the traditional understanding of biology or inheritance. Tending generated tension until the old fulcrum of biology was snapped in two.”

Out of Tenderness … Tension

“Tenderness and tension,” said Dr. Mukherjee, “the two qualities that I think define science. Tenderness has to do with the day-to-day life of a scientist… . When I witness science in action, I see this tenderness in abundance.”

“On Monday morning, the graduate students and postdoctoral fellows in my laboratory rush in to see how their cells have grown over the weekend. The best of these researchers have a gardener’s instinct: Some cultures need nourishment; some need to be left alone to inhabit the corners of incubators; and yet others need to be coaxed with growth factors to flourish… . “

And then, explained Dr. Mukherjee, “out of those years of tending comes tension — that spectacular crystallizing moment when all the pieces of a puzzle come together on the verge of making complete sense.”

The Addiction of Science

Speaking directly to the graduates, Dr. Mukherjee offered the following counsel: “First, as you go into the world, remember to tend whatever you do. Be tender. Grow things. Put your hand and mind to work.”

“Second, don’t ignore the tension. There’s a reason both words arise out of the same root, Latin for ‘stretch.’ Stretch yourself and cultivate the tension… . Third, take advice about what you can do but be careful about taking advice on what you cannot do.”

Here, he summoned personal experience: “Had I asked someone if I could write a 600-page book while running a lab and being a fellow, I know what I would have heard. My crucial advantage was, I didn’t ask!”

Finally, Dr. Mukherjee urged that the graduates not forget “the addiction” of science. “When you see the crystal, you forget the labor of growing it… . It is as if someone designed the perfect narcotic for a particular kind of addict.

“To experience it is — and I can only use an addict’s words here — to find a high that is so profound, so unique and powerful, so mesmerizing, that it makes the labor of getting to the high seem immaterial.”

The Medal for Outstanding Contributions to Biomedical Science

At the conclusion of his address, Dr. Mukherjee received the Memorial Sloan-Kettering Medal for Outstanding Contributions to Biomedical Science, which is awarded each year to the keynote speaker.

Memorial Sloan-Kettering’s Commencement and Academic Convocation honors students whose doctoral dissertation work was conducted in Memorial Sloan-Kettering laboratories, and students in the Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences receive their PhD degrees. In addition, younger Memorial Sloan-Kettering physicians, scientists, and postdoctoral research fellows, as well as established clinicians and investigators from Memorial Sloan-Kettering and beyond, are recognized.